As opposed to the consequences of elevated cholesterol, little is known about pathologies linked to the lack of cholesterol and gene defects of this metabolic path. Lanosterol 14a-demethylase CYP51 is the major regulatory enzyme of the post-squalene part of cholesterol synthesis. Defects in this gene have so far not been linked to human pathologies. There is neither known how the absence of one functional CYP51 allele influences the phenotype and to what pathological symptoms an inherited or an acquired defect of cholesterol synthesis in the liver can lead. Preliminary work on a limited number of transgenic mice with conditionally knockout Cyp51 gene reveals important differences between the sexes.

We aim to continue this research. We will define the role of heterozygosity on the Cyp51+/ mouse phenotype of both sexes. We will define the consequences of the Cyp51 knockout in the liver in mice of both sexes. We will search for polymorphisms of CYP51 gene at target patient populations. We will ascertain functional links between Cyp51 genotype/phenotype of transgenic mice and patients. We will examine biological samples of various transgenic mice, which will be fed with different diets (diet rich with lipids, or without cholesterol), with or without additional circadian rhythm desynchronization. We will screen DNA collections of target groups of patients, such as prematurely born children of both sexes from the study of our American collaborator in the project, and selected female and male patients from the Clinical Department of Endocrinology of the University Clinical Centre in Ljubljana.

We will apply experimental approaches of functional genomics (high-throughput analyses of transcriptome, SNP and sequencing, promotor analyses, metabolomics, determining blood parameters, western analysis, immunohistochemistry, etc.), bioinformatics, and data mining. These approaches will enable a holistic insight into the irregularities appearing due to deficient expression of Cyp51 and synthesis of cholesterol so that phenotypes of mice could be translated to the human. The approaches are original, being in conformance with the European directives of translational research as well as in conformance with the trends in the development of personalized medicine of the post-genomic era.